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Rischio cardiovascolareRoberto Miccoli

Endocrinologia e Metabolismo Università di Pisa

Diapositiva preparata da ROBERTO MICCOLI e ceduta alla Società Italiana di Diabetologia.

Per ricevere la versione originale si prega di scrivere a [email protected]

Il Dott. Roberto Miccoli dichiara di NON aver ricevuto negli ultimi due anni compensi o finanziamenti da Aziende Farmaceutiche e/o di Diagnostici

Dichiarazione di conflitto di interessi



Early onset ofCVD in men

More frequent evaluation of men

CVD as a “man’s disease”

Knowledge gap

Patient Physician

Inequities in health care access/process

Sub-optimal carefor at-risk women

Miccoli R. 2017

Sex-related differences in cardiovascular epidemiology



CVD remains the most common cause of death worldwide

The number of deaths from CVD is higher in women (2.2 million) than men (1.8 million), with CVD accounting for 49% of all deaths in women and 40% of all deaths in men.

Townsend N. European Heart Journal (2016) 0, 1–14

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Men

Women



http://www.istat.it/it/files/2014/12/Principali_cause_morte_2012.

Le malattie cardiovascolari sono la principale causa di morte nelle donne

1

34

123



Femmine

Maschi

Andamento della morbilità CV in Italia in base al sesso

http://www.salute.gov.it/imgs/C_17_pubblicazioni_2606_allegato.pdf



0

20

40

60

80

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Anno 1981 1983 1985 1987 1989 1991 1993 1995 1997 1999 2001 2003 2007 2009 2011

Men Women All

Andamento della mortalità CV per genere in Italia

http://www.istat.it/it/files/2014/12/Principali_cause_morte_2012.

Rate

/100

.000



Although CVD remains the leading killer of both women and men, there are substantial sex/gender differences in the prevalence and burden of different CVDs.

- Patterns of coronary artery plaque of women differ from that observed in men. (ShawLJ, JACC 2006)- Chest pain is less predictive of CAD in women than in men. (McSweeney JC, Circulation 2003)- Women admitted for acute coronary syndromes appear more likely than men to die in the hospital. (El-Menyar A, PLoS ONE 2013)- Women may be prescribed lipid-modifying agents and ACE inhibitors less than men (Bugiardini L, Eur. Heart J, 2011) and sex differences in drug prescriptions persist throughout the lifetime.- While the prevalence of heart failure is greater in men, women carry a higher mortality. (Go AS, Circulation 2014)

The incidence and prevalence of coronary heart disease and atherosclerotic diseases in noncoronary beds are higher in post-menopausal than in pre-menopausal women.

Menopause, age, and cardiovascular risk



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39-59 50-55 55-60 60-65 65-70 70-75 75-79 Total

Female Male

Cumulative 10-year total CVD by sex and age

Jørstad HT,et al.Heart 2015;0:1–6

Kapl

an M

eier

Rat

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Age group

n. 24 014 men and womenaged 39–79 years without baseline CVD or diabetes mellitus in the prospective population-based

European Prospective Investigation of Cancer and Nutrition-Norfolk (EPIC) cohort.

24,9%

18,4%



Risk of acute fatal CHD events by menopause category with men as referent group

Kim C. J Am Heart Assoc. 2015; 4:e001881

Model 1 adjusts for age and region. Model 2 adjusts for less than high school education and annual income <$35 000. Model 3 adjusts for level of total cholesterol, high-density lipoprotein cholesterol, systolic blood pressure, albumin-creatinine ratio, and C-reactive protein; current smoking (yes/no), diabetes (yes/no), never exercise (yes/no), use of antihypertensives (yes/no), and statins (yes/no). Model 4 further adjusts for estrogen therapy. Model 5 further adjusts for waist circumference (cm) and body mass index (kg/m2). Model 6 further adjusts for age at last menstrual period <45 years (yes/no). BSO indicates bilateral oophorectomy;



0

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39-59 50-55 55-60 60-65 65-70 70-75 75-79 Total

Female Male

Cumulative 10-year CVD/CVD mortality by sex and age

Kapl

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eier

Rat

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Age group

Jørstad HT,et al.Heart 2015;0:1–6

4,6%6,8%

n. 24 014 men and womenaged 39–79 years without baseline CVD or diabetes mellitus in the prospective population-based

European Prospective Investigation of Cancer and Nutrition-Norfolk (EPIC) cohort.



Increasing Risk of CVDMinimal or no CVD Risk

MenopauseTraditional Paradigm

Increasing Risk of CVD

Menopause

Alternative Paradigm

Changing the paradigm for cardiovascular disease and menopause



Menopause(and its associated loss of

endogenous estrogen)Biological ageing

Age-related cardiovascular risk

Cardiovascular risk in women

Menopausetiming



Effects of menopause on cardiovascular risk

Davis S. Nature Reviews 2015



Estrogens regulate insulin sensitivity

↓Estrogen

↑Food intake& fat accumulation

Central regulation of Energy Homeostasis

Peripheral Tissues Energy Homeostasis

↓ Glucose disposal↑Visceral fat

↓Insulin receptors↓Lipoprotein-lipase

↑Glucose production↑Inflammation↑TG accumulaton

↓Insulin-stimulated AKT-P

Adapted from Barros RPA, Cell Metabolism 14, 2011



Proposed Relationships between insulin resistance and factors that may predispose to atherosclerosis and CVD

Insulin resistanceHyperinsulinemia

Hyperglycemia

Hypertension

Monocyte activation

Oxidative stress• F2-isoprostanes• EO6 epitopes• Ox-LDL autoAb/IC

Endothelial dysfunction• Soluble adhesion

molecules• PAI-1

Altered fibrinolysis/coagulation• Fibrinogen • PAI-1• t-PA

AGE’s• AGE proteins• AGE autoAb/IC

Inflammation• Fibrinogen• CRP• PAI-1

Dyslipidemia• D-LDL• TGRL• Low-HDL



1,1

1,11

1,12

1,13

1,14

1,15

1,16

1,17

1,18

1,19

CHD Stroke CHD+Stroke

Model 1 Model 2 Model 3 Model 4

Model 1: Adjusted for age.Model 2: As model 1 plus confounder adjusted (life course socioeconomic position, smoking and physical activity).Model 3: As model 2 plus adjusted for other components of the metabolic syndrome (body mass index, waist-to-hip ratio, high density lipoprotein cholesterol, triglyceride levels, and systolic blood pressure) and LDL-c. Note: When waist circumference was used instead of waist-to-hip ratio none of the results changed from those presented.Model 4: As model 3 plus mutual adjustment for other exposures (fasting glucose, insulin, and HbA1c).

Independent Associations of Fasting Insulin,with Stroke and Coronary Heart Disease in Older Women

Lawlor DA. PLoS Medicine 2007; 4: 1396-1404

3,246 British women aged 60–79 y, free of baseline CVD and diabetesHR

per

1 S

D Fa

stin

g in

sulin



Comparison of insulin resistance (SSPG) in women and men by BMI and age

Kim SH. J Clin Endocrinol Metab 2013; 98: E1716–E1721

Cross-sectional study of women(n. 468) and men(n. 354) who had the measurement of CVD risk factors and steady-state plasma glucose (SSPG) concentration (insulin resistance) using the insulin suppression test



Menopause, insulin-stimulated glucose uptake and CVD risk

Cardiovascular risk score Glucose disposal*

* Glucose uptake (M), determined by the euglycemic hyperinsulinemic clamp technique

Manco M. Menopause 2006; 13: 809-817

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European Group for the Study of Insulin Resistance database -clamp data pooling projectn. 523 normal and overweight women



Insulin sensitivity parameters

Estimated coefficients of correlation of Cardiovascular Risk Score with glucose disposa (M)l

• Menopause does not seem to strictly relate to a decrease in insulin sensitivity as postmenopausal women had the same insulin sensitivity as age-matched men. • In the population studied, the best predictor of CV Score was fasting insulin rather than insulin sensitivity.

Menopause, insulin-stimulated glucose uptake and CVD risk

Manco M. Menopause 2006; 13: 809-817



Commento

Alcun studi hanno dimostrato che l’insulino resistenza si associa a (deboleo moderato) aumento del rischio cardiovascolare in menopausa, ma irisultati che tengono conto dei fattori confondenti sono inconsistenti.

Gli studi sono in gran parte osservazionali retrospettivi, di piccoledimensioni o con follow-up brevi.

Non è noto se le misure di insulino resistenza possano migliorare lapredizione del rischio cardiovascolare.



The Woman Health Initiative (WHI): 15.288 postmenopausal women - median age 64 years (25th–75th percentiles 58–69 years) - mean follow-up 9.2 years

CV risk prediction by insulin resistance in postmenopausl women

Schmiegelow MD. Circ Cardiovasc Qual Outcomes. 2015;8:309-316



CV risk prediction by insulin resistance in postmenopausl women

HRs for development of cardiovascular disease C index for discriminative CV prediction

Schmiegelow MD. Circ Cardiovasc Qual Outcomes. 2015;8:309-316



Commento

I marker di insulino resistenza (insulinemia, HOMA-IR, TG/C-HDL) sono associati ad aumento del rischio CV nelle donne in menopausa, in analisi aggiustate solo per età e etnia.

Nessuna di queste misure fornisce informazioni prognostiche aggiuntive rispetto ai fattori di rischio tradizionali, in particolare il C-HDL.

Sebbene l’insulino resistenza svolga un ruolo importante nello sviluppo dell’aterosclerosi, l’informazione fornita dalla sua misura appare essere catturata dai fattori di rischio tradizionali nelle donne in post-menopausa senza precedenti CV.



Proposed Relationships between insulin resistance and factors that may predispose to atherosclerosis and CVD

Insulin resistanceHyperinsulinemia

Hyperglycemia

Hypertension

Monocyte activation

Oxidative stress• F2-isoprostanes• EO6 epitopes• Ox-LDL autoAb/IC

Endothelial dysfunction• Soluble adhesion

molecules• PAI-1

Altered fibrinolysis/coagulation• Fibrinogen • PAI-1• t-PA

AGE’s• AGE proteins• AGE autoAb/IC

Inflammation• Fibrinogen• CRP• PAI-1

Dyslipidemia• D-LDL• TGRL• Low-HDL



Miccoli R. Future Lipidol. 2008; 3: 651–664

Insulin resistance & atherogenic dyslipidemia



Changes in lipids and apolipoptoteins during menopausal transition

Mattews KA. J Am Coll Cardiol. 2009; 54: 2366–2373

SWAN (Study of Women’s Health Across the Nation) - 3.302 women - after 10 annual examinations,1,054 women had achieved an FMP



Lipoprotein subclasses and coronary artery calcium in postmenopausal women from the Healthy Women Study

Coronary artery calcification (CAC) by electron beam computed tomography, andlipoprotein subclasses by NMR spectroscopy - 286 healthy women (mean age 61.7), at 8 years postmenopause

• Small LDL, higher levels of LDL particles, and large VLDL were each positively associated (p <0.05) with higher CAC after adjustment for age, systolic blood pressure (SBP), current smoking, and conventional measures of LDL cholesterol, HDL cholesterol, and triglycerides.

Mackey RH. Am J Cardiol 2002;90(suppl):71i–76i



Cholesterol Efflux Capacity and Subclasses of HDL Particles in Healthy Women Transitioning Through Menopause

SWAN study: Longitudinal study: before and after menopause as indexed by the final menstrual period46 women, mean baseline age 47.1

El Khoudary SR. J Clin Endocrinol Metab 101: 3419–3428, 2016

Large HDL-PIMA and CEC increased significantly in the early phase of the menopausal transition.



Longitudinal:

• BP increase during follow-up

• Cardiovascular mortality and morbidity were greater in menopausal than in fertile women, and comparable in menopausal women and men, a difference no longer present in age-matched cohorts.

Menopause does not affect blood pressure and risk profile, and menopausal women do not become similar to men

*P < 0.001 vs. fertile women. BP, blood pressure.

Casiglia E. J Hypertens 26:1983-1992

9364 representative men and women aged 18-70 years recruited from Italian general population



Variation of the effect of menopausal status, systolic blood pressure, and pulse pressure on the presence of coronary artery disease

• Age-adjusted differential relationships between PP and SBP and menopausal status were found.

• Both interaction effects remained significant even after adjustment for age, suggesting independent risk contribution from both age and menopausal status.

Gierach GL. J Am Coll Cardiol 2006;47:50S-8S

Women’s Ischemia Syndrome Evaluation (WISE): 123 premenopausal and 482 postmenopausal women undergoing coronary angiography for suspected ischemia



Systolic blood pressure and pulse pressure are potent risk factors for CAD in the premenopausal women

Women’s Ischemia Syndrome Evaluation (WISE): 123 premenopausal and 482 postmenopausal women undergoing coronary angiography for suspected ischemia

Gierach GL. J Am Coll Cardiol 2006;47:50S-8S



Increased visceral fat during the menopausal transitionObservational, longitudinal study with annual measurements for 4 years - 156 women

• Fat and lean mass (dual-energy X-ray absorptiometry), visceral (VAT) and subcutaneous abdominal fat (SAT) (computed tomography),

Lovejoy JC. Int J Obes 2008 ; 32: 949–958.



Echocardiographic epicardial fat thickness and insulin resistanceN. 246 consecutive subjects (120 women,

126 men, median age 46 years (30–65), median BMI 32 kg/m2 (22–52)

Iacobellis G. Obesity 2008; 16: 887–892



Late peri-/postmenopausal women have greater volumes of heart fat

Study of Women’s Health Across the Nation (SWAN) Heart andCardiovascular Fat Ancillary Study - Cross-sectional and longitudinal study designs 456

women (mean age, 50.75 y) - Computerized tomographic scans to quantify CF depots

EAT, epicardial adipose tissue; PAT paracardial adipose tissue; TAT total heart adipose tissue; PVAT, perivascular adipose tissue

El Khoudary SR. Clin Endocrinol Metab 2015; 100: 3304–3312



Early menopause and type 2 diabetes riskInterAct study (EPIC cohort) - 3,691 postmenopausal type 2 diabetic case subjects

and 4,408 subcohort members - median follow-up of 11 years.

Brand JS. Diabetes Care 2013; 36:1012- 1019



Commento

Le alterazioni del profilo lipidico si verificano all’inizio della perimenopausa e nelle fasi precoci della postmenopausa. Alcune di queste alterazioni sono predittive di malattia cardiovascolare clinica o subclinica.

Il passaggio dall’età fertile alla menopausa si accompagna ad un incremento della pressione arteriosa, ma tale fenomeno sembra dipendere soprattuto dall’aumento dell’età. L’identificazione precoce dell’ipertensione nelle donne in perimenopausa dovrebbe spingere ad ulteriori valutazioni del rischio cardiovascolare.

La menopausa si associa a incremento del grasso corporeo totale e del grasso viscerale. L’aumento del grasso cardiovascolare potrebbe contribuire al rischio cardiovascolare.

La transizione menopausale non sembra avere una forte influenza sui livelli di insulina e glicemia. Le donne con menopausa precoce hanno un elevato rischio di sviluppare diabete tipo 2.Diapositiva preparata da ROBERTO MICCOLI e ceduta alla Società Italiana di Diabetologia.


Progression and outcomes of metabolic syndrome

Abdominal obesity

IGR↑TG

↓HDL-CHypertension

Type 2 diabetesCardiovascular disease

Diabetes complications

Adapted from Grundy SM, J Am Coll Cardiol 2006; 47:1093–100

Multipleborderline risk factors

Multiplecategoricalrisk factors

Plasma glucoseTriglycerides

HDL-CBlood pressure



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20-29 30-39 40-49 50-59 60-69 ≥70

Age (years)

Men N. 940

Women N. 1160

Prev

alen

ce (%

)Prevalence of metabolic syndrome by age

The “Lucca Cuore” Study

Miccoli R, Nutr Metab Cardiovasc Dis 2005

18%15%



Menopause and the Metabolic SyndromeThe Study of Women’s Health Across the Nation

Longitudinal, 9-year study of 949 participants - 5 ethnicities at 7 geographic sites - Age 50.9

Janssen I. Arch Intern Med. 2008;168(14):1568-1575

* MetS: modified National CholesterolEducation Program Adult Treatment Panel III definitionwith 100 mg/dL as the cut point for glucose level

• By the final menstrual period, 13.7% of the women had new-onset MetS.

• Odds of developing the MetS per year in perimenopause were 1.45 (95% confidence interval, 1.35-1.56); after menopause, 1.24 (95% confidence interval, 1.18-1.30). These odds were significantly different(P.001).



The change in the MetS components with the transition from perimenopause to postmenopause (afteradjusting for covariates)

Janssen I. Arch Intern Med. 2008;168(14):1568-1575



0

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60

80

100

120

Premenopause Postmenopause

≥1 ≥2

≥3 ≥4

OR* P value

2.79 0.0001

1.35 0.087

1.51 0.030

2.20 0.002

Hee MK, Diabetes Care 2007; 30:701–706

N. O

f co

mpo

nent

s (%

)

* Age Adjusted

Prevalence and age-adjusted ORs of risk factors of the metabolic syndrome among premenopausal and postmenopausal women who did not receive

hormone replacement therapy



A random population sample of 394 women aged 45–54 years

Clustering of metabolic syndrome components and population changes in insulin resistance during menopausal transition

The acceleration of MS incidence at the onset of menopause may be accompanied by an increase in insulin resistance only in the population at highest risk. Reproductive women entering the menopause with an isolated MS component are at high risk for developing additional risk factors during menopause.

Lejskova M. Climateric 2011; 14: 83-91



Hazard associated with the MetS for cardiovascular mortality rate is greater in women

San Antonio Heart Study - 2815 participants, 25 to 64 years of age

Circulation. 2004;110:1251-1257



Commento

La transizione menopausale si associa ad incremento della prevalenza della sindrome metabolica.

L’incidenza della sindrome metabolica aumenta con il peggiorare della sensibilità insulinica (elevati valori di HOMA-R).

Le donne con sindrome metabolica hanno un rischio elevato di sviluppare diabete e CVD.

La stima del rischio cardiovascolare in menopausa non può basarsi solo sulle componenti della sindrome metabolica, ma deve considerare tutti i fattori di rischio.



Cardiovascular risk

Life-style intervention(physical activity, healthier diet, tabacco cessation)

Obesity HypertensionAtherogenic dyslipidemiaHyperglycemia

• Liraglutide• Bariatric surgery

• ACEIs• ARBs• Other drugs

• Statins (±ezetimibe)• PCSK9i• Fibrates

• Metformin• Pioglitazone• Incretin mimetics,DPP4i, glifozinsor insulin

Body weight reduction:7-10%

Diabetes prevention

If diabetes is present:HbA1c<7%

Very high CV risk:LDL<70 mg/dlHigh CV risk:

LDL<100 mg/dlModerate CV risk:

LDL<130 mg/dlLow CV risk:

LDL<160 mg/dl

Blood pressure <140/90 mmHg

If diabetes is present:<130/80 mmHg

The problem

Therapeutic step 1

Residual CV risk factors

Therapeutic step 2

Goals

Modificato da: Bianchi C. Miccoli R Expert Rev Cardiovasc Ther 2007; 5:491–506



• La transizione menopausale rappresenta un periodo di importanti cambiamenti peggiorativid dei fattori di rischio cardiovascolare.

• Il contributo di fattori di rischio multipli, spesso accumunati dall’insulino resistenza, nel contesto della menopausa e dell’invecchiamento, rendono complessa la relazione menopausa-malattie cardiovascolari. • Alcuni indici di insulino resistenza si associano al rischio cardiovascolare quando considerati isolatamente; le associazioni sono fortemente attenuate se si tiene conto dei fattori di rischio tradizionali. • La sindrome metabolica non offre sostanziali vantaggi nella predizione del rischio CV (e del diabete) in menopausa. Se questa sindrome nel suo insieme pesi più della somma dei tratti non è dimostrato.

• Gli interventi sullo stile di vita ed il trattamento farmacologico di alcuni fattori di rischio (colesterolo LDL, ipertensione, iperglicemia, obesità) dovrebbero essere implementi prima della transizione menopausale per contrastare il loro peggioramento e ridurre il rischio di eventi cardiovascolari.

Conclusioni



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